Whatever the effect or pathway, all manual therapy techniques share a common denominator: the transfer of force to internal tissues. While spinal manipulative therapy (SMT) and mobilization (MOB) are the most common forms of manual therapy, the impact of these treatments on spinal tissues is completely unknown. By combining innovations in robotics, mechanobiology, and molecular biology, we propose a novel approach to delineate the biological mechanisms underlying the most common physical intervention for back pain: manual therapy. This project will evaluate (1) the loads in spinal tissues during manual therapy and (2) the biomarker response of tissues experiencing these loads. This approach aims to bypass years of trial-and-error investigation by identifying specific tissue responses induced by manual therapy. The project's hypothesis is that loads generated by manual therapy induce specific biological responses in spinal tissues. Aim 1 quantifies vertebral kinematics in response to SMT and MOB when applied to an in vivo porcine model. Aim 2 quantifies the change in motion segment loads and moments during SMT and MOB due to loss of discrete spinal tissues. Aim 3 compares the mechanobiological responses of the tissue of interest (identified in Aim 2) whose loss results in the greatest change in motion segment load and moment. We expect that SMT and MOB affect spinal tissues differently. Tissues whose loss creates the greatest change in motion segment loads and moments caused by SMT and MOB will have proportionately greater mechanobiological responses to manual therapies when compared to controls. By identifying the tissue-specific effects of SMT, we can begin to expose the biomechanical and neurophysiologic mechanisms underlying manual therapies. This knowledge will help clinicians understand the biological basis for tissue-specific therapies and help identify patients who will benefit most (or who are at risk) from SMT and MOB. Ultimately, we aim to discover sensitive, tissue-specific biomarkers as an index of SMT efficacy, tools that do not exist presently. PUBLIC HEALTH RELEVANCE: More than arthritis, back pain creates the largest burden of musculoskeletal disability and expense. Toward reducing this burden, new knowledge is needed but has been blocked by a lack of effective back pain therapies and tools to measure spinal function. These problems suggest that we need new ways of investigating back pain and its treatment. By combining several new technologies and concepts, we will conduct novel investigations into the biological mechanisms underlying the most common physical intervention for back pain: manual therapy. By understanding how manual therapy works, we can better define who will benefit from it (and who will not). This information will not only help to reduce the tremendous cost and morbidity of back pain, but lead us toward understanding the causes of back pain itself.